Hedgehog Signaling Plays a Conserved Role in Inhibiting Fat Formation

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The involvement of hedgehog (Hh) signaling in cell determination and differentiation in a wide variety of tissues in both invertebrates and vertebrate has been well established. However, relative little is known about its function in formation of adipose tissues. To address this question, Drosophila and mammalian models were used to analyze its potential role. Components of the Hh pathway were expressed in the Drosophila fat body. Activating Hh signaling specifically in fat body inhibited fly fat formation. Conversely, blocking Hh signaling specifically in fat body stimulated fly fat formation. Analysis in mammalian models suggested the presence of functional Hh signaling in murine developing fat, adult fat and in mammalian adipogenic models. Down-regulation of Hh signaling marked the stage of terminal differentiation. In 3T3-L1 preadipocyte cell line, addition of recombinant murine sonic Hh (Shh) potently inhibited adipogenic differentiation dose-dependently, resulting in decreased intracellular triglyceride accumulation and reduced mRNA levels of established adipogenic genes. Treatment of KAAD-cyclopamine, an antagonist of Hh signaling, promoted adipogenesis. Activating or blocking Hh signaling genetically produced similar effects as pharmacological treatment. Additional study in multipotent cell lines, NIH3T3 and C3H10T1/2, reinforced the inhibitory role of Hh signaling in adipogenesis. However, the inhibition was effective only when Hh signaling was activated during early stage of adipogenesis. Epistasis tests suggested Hh signaling functioned upstream of PPARgamma . Mechanistic studies showed that Hh signaling might act as a molecular switch, likely mediated by anti-adipogenic transcrition factors such as GATA2, to divert preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis to osteogenesis. My study on the function of Hh signaling in fat formation of both invertebrates and vertebrates suggested that Hh signaling played a conserved role in inhibiting fat formation and highlighted the potential of the Hh pathway as a therapeutic target for osteoporosis, lipodystrophy, diabetes and obesity.